Immunotoxins are a class of pharmacologic reagents in which monoclonal antibodies are linked to potent toxins such as ricin, pokeweed antiviral protein (PAP), or saporin. We will develop and characterize a panel of immunotoxins for use in clinical bone marrow transplantation. Bone marrow transplantation has become the preferred treatment for a number of hematologic diseases, and most notably, for certain types of acute and chronic leukemias. In allogeneic bone marrow transplants, immunocompetent T cells that cause graft-versus-host disease can be purged from donor grafts by using immunotoxins prior to infusion. In autologous bone marrow transplants, contaminating leukemia cells can be removed from remission autografts prior to autologous rescue. This grant will primarily be directed towards synthesizing the most selective and potent immunotoxins against normal and leukemic lymphocytes. We will optimize pretreatment protocols for ex vivo treatment of bone marrow and investigate the ability of various chemical potentiators to improve the activity of our reagents. We will develop a panel of immunotoxins against T-lineage cells which can be used for allogeneic bone marrow transplantation and autologous bone marrow transplantation of patients with T-cell leukemias. A panel of anti-B cell immunotoxins will be developed for autologous bone marrow transplantation for B leukemias/lymphoma. A panel of antimyeloid immunotoxins will be used for autologous bone marrows transplantation of patients with myelogenous leukemia. We will also attempt to synthesize new immunotoxins for in vivo therapy. Our studies will focus on immunotoxins made from phytotoxins which represent a class of naturally occurring A chains having no reactivity with the surface of human cells but high reactivity inside the cytosol. We will test these reagents to determine their usefulness in treatment of residual disease. These studies will provide information of great clinical value leading to the development of new protocols for the University of Minnesota Bone Marrow Transplantation Program. (TT)